Due to the development of genetic recombination techniques, the market for protein pharmaceutical products such as therapeutic proteins and antibody drugs has rapidly expanded. In particular, antibody drugs can have high specificity without causing an adverse immunoreaction when administered to the human body, and therefore, the development thereof has been actively pursued.
As a host by which a pharmaceutical protein product typified by an antibody drug is produced, a microorganism, a yeast, an insect, an animal or plant cell, a transgenic animal or plant cell, or the like can be used. In order for the pharmaceutical protein product to have biological activity or immunogenicity, post-translational modification such as folding or glycosylation is essential. Therefore, a microorganism with which complicated post-translational modification cannot be performed, or a plant having a different glycan structure, is not suitable as the host. The use of a cultured mammalian cell such as a CHO (Chinese hamster ovary) cell, which is from a species closely related to humans, is the current standard considering that such a cell has a glycan structure similar to that of humans and is safe, and post-translational modification can be performed using such a cell.
In cases where a cultured mammalian cell is used as the host, there are problems that the growth rate is low, the productivity is low, the cost is high, etc., as compared with a microorganism or the like (NPL 1). In addition, in order to use a pharmaceutical protein product clinically, it is necessary to administer a large amount of the product. Therefore, the lack of production ability thereof is another worldwide problem. When a pharmaceutical protein product is produced in a cultured mammalian cell expression system, the production cost is high as compared with a low molecular weight synthetic pharmaceutical product. Accordingly attempts have been made to reduce the production cost by improving the respective production steps. Improvement of the production amount in the cultured mammalian cell expression system is an effective method for reducing the production cost (NPL 2 and NPL 3). Accordingly, in order to improve the productivity of a foreign gene in a cultured mammalian cell, various approaches based on promoters, enhancers, antibiotic selection markers, gene amplification, culturing engineering techniques, and the like have been investigated. In cases where a CHO cell is used as a host cell to express a foreign gene, i.e., to produce a pharmaceutical protein product, a virus-derived, human cytomegalovirus major immediate early promoter (hereinafter referred to as “CMV promoter”) is generally used (NPL 4, NPL 5, and NPL 6). Further, it is known that a polynucleotide upstream of the transcription start site of a human ribosomal protein gene such as RPL32 or RPS11 can be used as a DNA element for the protein expression in a CHO cell, in combination with another heterologous promoter (NPL 7 and PLT 1).